Cancers of the colon and rectum (CRC), the second leading cause of cancer death in the US, can be detected at an early, more curable, stage or even prevented using available screening techniques. Although some expert groups in the US consider colonoscopy to be the standard, there is currently only limited direct evidence to support its increasing use for screening in average risk adults. Colonoscopy has higher risks and costs than other screening tests. Recent studies reported that colonoscopy did not reduce mortality from right-sided colon cancers, the part of the colon that is beyond the reach of sigmoidoscopy. However, those findings were controversial because that study was unable to distinguish screening from diagnostic uses or accurately assess the completeness of colonoscopies. This project's goal is to inform clinical and policy decisions by providing evidence to show whether the purported benefits of colonoscopy are realized in practice. The primary specific aim is to estimate the effectiveness of screening colonoscopy in reducing death from CRC among average-risk adults when compared to no screening, overall and separately for right- and left-sided cancers. Our secondary aims are to: 1) determine the impact of the completeness of colonoscopy examinations on its effectiveness; and 2) compare the effectiveness of screening colonoscopy relative to sigmoidoscopy. We will use a case-control design nested in an historical cohort of persons receiving care at 3 sites participating in a research consortium, Cancer Research Network (CRN). These sites provide the full continuum of cancer care to their members ranging from screening through end of life care, and provide access to information on CRC screening that can be linked to diagnosis and cause-specific mortality data on large numbers of racially and socioeconomically diverse persons. We will identify at least 1,200 cases of CRC deaths between 2007 and 2014 among enrollees who were 52 years or older at the date of the diagnosis, each matched within each health plan to two randomly selected controls based on age, sex and enrollment history. We will identify screening history for a minimum of 10 years prior to cancer diagnosis, differentiating screening from diagnostic procedures, using standardized targeted chart reviews and other sources. The sample size will provide sufficient power for separate evaluations of tumors located in the right colon. This project will be carried out by an experienced interdisciplinary team representing epidemiology, case-control methodology, biostatistics, gastroenterology and primary care. Team members are national leaders in CRC screening research and policy. This project is in synergy with existing NCI and the CRN goals to: 1) develop methods and approaches to provide clinical, policy-relevant information; and 2) inform clinical and public health decisions on CRC screening. This application is also responsive to the NCI's priority to improve understanding of the effectiveness and comparative effectiveness of tests used in screening for CRC, a health disparity condition, and addresses Healthy People 2010 goals to reduce cancer death.